Smad3 is involved in the intracellular signaling pathways that mediate the inhibitory effects of transforming growth factor-β on StAR expression

Transforming growth factor beta s (TGF beta s) constitute a family of dimeric proteins that regulate growth and differentiation of many cell types. TGF beta 1 is also a potent autocrine regulator of adrenocortical steroidogenesis. We have recently shown that in primary cultures of bovine fasciculo-reticularis cells, the main target of TGF beta is the steroidogenic acute relay protein (StAR), a key protein necessary for intramitochondrial cholesterol transport, Here, we show that StAR expression is also inhibited by TGF beta 1 in the human adrenocortical carcinoma cell line NCI-H295R. This inhibitory effect is mediated by Smad proteins. Indeed, we found that overexpression of wild-type Smad3 inhibited endogenous StAR mRNA expression while overexpression of a dominant negative Smad3 protein reversed the inhibitory effect of TGF beta 1 on StAR mRNA expression. Taken together, these results demonstrate that the Smad3 protein is involved in TGF beta-dependent regulation of steroidogenesis. (C) 1998 Academic Press.